OVERALL ? PROJECT SUMMARY/ABSTRACT This is a competing continuation for a grant entitled ?Biomarkers of Cognitive Decline Among Normal Individuals: The BIOCARD Cohort? (FOA: PAR-18-296). This study, known as the BIOCARD study, is a longitudinal, observational study of 349 individuals who were cognitively normal and primarily middle aged (mean age=57.1) at enrollment. By design, two-thirds had a family history of Alzheimer?s disease (AD). The primary goal was to follow individuals from normal cognition to mild cognitive impairment (MCI) or dementia, so that it would be possible to identify biomarkers that predicted progression. The BIOCARD study is in a unique position to examine the ?preclinical? phase of AD, since the participants: (1) have been followed for up to 27 years (mean follow-up = 15.2 yrs.), (2) are continuing through the period of accelerating risk, and (3) 64 of those alive have MCI or dementia. Our overall objectives are to further advance the study of preclinical AD by: (1) clarifying the pattern and rate of change in AD biomarkers (including those based on CSF, blood, MRI, and PET imaging) and cognition; the biomarkers to be studied include several promising novel biomarkers derived from blood, CSF and brain imaging. (2) maximizing our data by working collaboratively with several research groups who have comparable data, and (3) providing a publicly accessible data, brain scans, and biological specimens, for researchers in the field. The long duration of follow-up for the cohort is based on the fact that the study was established in 1995 by investigators in the intramural program of the NIH. The study was stopped for administrative purposes in 2005. Our investigative team was funded in July 2009 to re-enroll the participants and re-initiate longitudinal data collection. Longitudinal follow-up was continued with our grant renewal in 2014. With this application, we are requesting funds to continue the longitudinal assessments which include: clinical and cognitive assessments, CSF, blood, MRI scans, and amyloid PET (using [11-C] PiB) and to initiate Tau PET (using [18 F] MK-6240), in the participants who remain cognitively normal (n=198, mean age = 70.9). We are also proposing to recruit an additional 150 subjects to increase the diversity of the participants and to expand the number of middle age subjects who can be followed with state-of-art- techniques. The rich data to be acquired will provide continued insights into the preclinical phase of AD.